Glaucoma impairs the vision of millions people worldwide and is one of the leading causes of blindness. Accounting for a significant number of patient visits to ophthalmologists' offices in North America, hundreds of thousands of new cases of glaucoma are diagnosed in the United States each year with many of those cases afflicting those of the older population. In fact, the annual cost of glaucoma has reached billions of dollars in the United States alone.
In open angle glaucoma, the most frequent form of glaucoma, visual field loss is caused by progressive optic nerve fiber deterioration due to the death of retinal neurons. Those retinal neurons, called retinal ganglion cells (RGCs), make up the inner retinal cell layers of the optic nerve. Concomitant with the progressive death of RGCs is an elevation of intraocular pressure (IOP) in the eye. This ocular hypertension is detected in the majority of glaucoma patients at some point in the disease.
It is believed that exposure to high IOP induces the chronic and progressive apoptotic death of RGCs at a constant weekly rate. Thus, glaucoma is a slow, chronic, and progressive neurodegenerative disease of RGCs. The IOP of those with glaucoma measures, on average, at levels that are 1.4 to 1.7 fold higher than the IOP of those without glaucoma. However, glaucoma is difficult to treat because the exact onset of high IOP is unpredictable and generally unapparent until peripheral vision loss occurs, at which point irreversible RGC loss is often advanced. Thus, glaucoma is primarily indolent with peripheral loss of vision generally only becoming clinically evident when most of the optic nerve axons are lost.
The mainstream treatment for glaucoma is the pharmacological reduction of high IOP back to near normal IOP levels. However, despite the normalization of IOP, sustained RGC death and clinical evolution towards glaucoma often continue, which suggests that high IOP may not be the direct cause of RGC apoptosis. Thus, exactly how ocular hypertension leads to the triggering of biochemical events that result in RGC apoptosis is unknown.
Current mechanisms proposed for RGC apoptosis in glaucoma include (i) excitotoxic damage (hyperactive NMDA receptors, elevated glutamate, Ca++ fluxes, and nitric oxide) (ii) ischemic or mechanical retinal injury leading to activation of microglia and macrophages which cause bystander damage of neighboring retinal cells and (iii) mechanical compression of the optic nerve head preventing axonal transport required for RGC survival (also known as “cuffing” or “physiologic axotomy”). However, these mechanisms alone can not explain why only RGCs should be susceptible to apoptosis instead of all cells in the inner retinal layer that are exposed to the potentially deleterious effects of altered glutamate/nitric oxide/Ca++ and to mechanical stress. Neither do these hypotheses explain why the normalization of IOP does not result in the complete arrest of RGC death when axonal transport is restored.
Thus, although high IOP is clearly correlated with RGC death in glaucoma, virtually no links have been made at the molecular level between high IOP and RGC apoptosis. As current glaucoma therapies which reduce IOP often do not prevent continued loss of RGC cells and deterioration of the optic nerve, what is needed are therapies that treat the molecular causes of glaucoma progression.